DDAH As a Novel Target in Pulmonary Fibrosis

DDAH 作为肺纤维化的新靶点

• 批准号: 8849498
• 负责人: Yohannes T Ghebre
• 金额: $ 13.16万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-26 至 2016-02-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8849498
• 关键词: Aerosols; Alveolar; Animal Model; Animals; Apoptosis; Architecture; Area; Attenuated; Basic Science; Binding; Biological Assay; Biology; Biomedical Research; Bleomycin; Blood specimen; Breathing; California; Cardiopulmonary; Cardiovascular Physiology; Cell Culture Techniques; Cell Proliferation; Cells; Cessation of life; Charcoal; Chemicals; Chronic; Chronic lung disease; Collaborations; Collagen; Communities; Conduct Clinical Trials; Core Facility; Data; Dedications; Deposition; Development; Disease; Drug Formulations; Drug Targeting; Elements; Environment; Enzymes; Epithelial; Epithelial Cell Proliferation; Etiology; Event; FDA approved; Faculty; Feasibility Studies; Fellowship; Fiber; Fibroblasts; Fibrosis; Fruit; Future; Goals; Hamman-Rich syndrome; Human; Human Resources; Inflammatory; Intention; Investigation; Journals; Kinetics; Laboratories; Lead; Life; Link; Lung; Lung Compliance; Lung Inflammation; Lung diseases; Measures; Mediator of activation protein; Mentored Research Scientist Development Award; Mentors; Modeling; Molecular; Mus; National Heart, Lung, and Blood Institute; Nitric Oxide Synthase; Outcome Study; Oxygen; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Physiology; Plasma; Play; Process; Proteins; Proton Pump Inhibitors; Publications; Pulmonary Fibrosis; Pulmonary artery structure; Recombinants; Research; Research Personnel; Research Proposals; Respiration; Respiratory physiology; Role; Safety; Scientist; Seminal; Smoke; Smooth Muscle Myocytes; Socioeconomic Status; Structure; Structure of parenchyma of lung; Surface Plasmon Resonance; Testing; Therapeutic; Tissues; Tobacco; Toxic effect; Transgenic Mice; Translating; Translational Research; Tuberculosis; Type II Epithelial Receptor Cell; Universities; Ursidae Family; Validation; Wood material; Work; abstracting; analog; base; bench to bedside; career; career development; cytokine; design; dimethylargininase; drug development; drug discovery; high throughput screening; improved; in vitro activity; indium-bleomycin; inhibitor/antagonist; innovation; insight; interest; large scale production; lung injury; mouse model; novel; novel therapeutics; programs; pulmonary function; screening; small molecule; stem; therapeutic development

DESCRIPTION (provided by applicant): Candidate: I am an underrepresented scientist proposing an area of research that is of primary interest to the NHLBI (pulmonary research). My keen interest in pulmonary diseases research stems from having lived in an area where chronic lung-related diseases (such as tuberculosis; active- and secondhand- tobacco-smoke as well as wood- and charcoal- smoke related ailments) are endemic due to the poor socio-economic status of the people. As such, I am currently supported by the Tobacco-related Disease Research Program (TRDRP) of the University of California to pursue an important research in this area. During this fellowship, I worked on a project that aimed to conduct high throughput screen (HTS) of small molecules to modify the enzymatic activity of dimethylarginine dimethylaminohydrolase (DDAH); an enzyme involved in cardiovascular physiology by modulating the nitric oxide (NO) synthase (NOS) pathway. I worked diligently with my mentor, Dr Cooke, to design an approach for large-scale production of recombinant DDAH and an assay to conduct the HTS. As described in our recent publication in the journal of Biomolecular Screening, our strategy bear fruit by discovering several novel small molecules that regulate DDAH enzymatic activity. This was particularly very exciting to me as DDAH has been shown to be principally involved in the progression of pulmonary fibrosis in a murine model of lung injury and was found to be upregulated in lung tissues from idiopathic pulmonary fibrosis (IPF) patients. These two important links: DDAH and its role on IPF, and the discovery of small molecules to regulate DDAH activity, fueled my interest in pursuing the development of a novel therapy to restore lung function. Environment: As described in my proposal, my research is significantly accelerated due to it being conducted at Stanford; a superb research environment with multiple core facilities for pharmacological, molecular and cellular studies. In addition, Stanford nurtures multi-disciplinary collaborations and highly committed to translating basic research into clinically useful therapy. Two examples of such bench-to-bedside translational research programs at Stanford are the SPARK and the Bio-X Research Programs. One of the areas that may benefit from such translational research efforts is IPF. At Stanford, there are groups who are actively working towards understanding the pathobiology of IPF and the development of potential therapeutics. One of these groups is my co-mentor, Dr Rosen's, lab that is working on a different target to treat IPF. Their expertise in this area will be valuable i my project. Furthermore, Stanford offers several relevant courses and seminars including Cardiopulmonary Research-in-Progress; Drug Development, and Future Faculty which are of great interest for my career development. Research: IPF is an aggressive and incurable disease that progressively destroys the normal architecture of the lung. Although, the precise etiology and sequence of events in the development and progression of IPF remains incompletely characterized, emerging data indicates that dysregulation of DDAH activity might play crucial role in the pathogenesis of this disease. Recent mechanistic study in an animal model of bleomycin- induced IPF-like lung injury, validated by lung tissues from IPF patients, indicates that DDAH is centrally involved in the disease process. Remarkably, treatment of bleomycin-challenged mice with DDAH inhibitor (L- 291) ameliorated fibrosis and restored lung function. Moreover, analyses of human lung tissue showed that DDAH was significantly elevated in IPF. Therefore, targeting this pathway might have some therapeutic potential as described in my research proposal. One way of regulating DDAH over-activation is by using small molecule antagonists that directly inhibit its enzymatic activity. Therefore, our discovery and validation o several small molecule antagonists of DDAH (including FDA approved ones (for other indication)), deserves further investigation for therapeutic development. Career goals: Practically, drug development is a lengthy process (12 years on average) that requires fundamental understanding of disease mechanisms and optimization of drug-leads to selectively and efficiently target the disease of interest. Therefore, my immediate-term goal is to study the feasibility of DDAH as a drug target in IPF using small molecule-based approach. If the outcome of this study is encouraging, I will then aim for my long-term career goals to conduct step-wise optimization of the drug-leads by forming a network of collaborations to synthesize and test several analogs of the most promising compounds and decipher the mechanism by which such drug-leads regulate DDAH activity. I plan to continue the drug discovery and development path with the ultimate goal of conducting clinical trials and developing a therapy for chronic pulmonary diseases in general and IPF in particular. Therefore, this Research Scientist Development Award from NHLBI will provide me an unparalleled opportunity to develop my career in Biomedical Research and bring innovation to the scientific community. The proposed research is in an area of primary interest to the NHLBI and is feasible given Stanford's research environment and the dedication and expertise of all the personnel tapped in this project. (End of Abstract)

描述（由申请人提供）：候选人：我是一个代表性不足的科学家，提出了一个研究领域，这是主要利益的NHLBI（肺研究）。我对肺部疾病研究的浓厚兴趣源于我生活在一个慢性肺部相关疾病（如肺结核;主动和二手烟草烟雾以及木材和木炭烟雾相关疾病）流行的地区，这是由于人们的社会经济地位低下。因此，我目前得到了加州大学烟草相关疾病研究计划（TRDRP）的支持，在这一领域进行重要的研究。在这个奖学金期间，我从事了一个项目，旨在进行高通量筛选（HTS）的小分子，以改变二甲基精氨酸二甲氨基水解酶（DDAH）的酶活性;一种通过调节一氧化氮（NO）合酶（NOS）途径参与心血管生理学的酶。我和我的导师Cooke博士一起努力设计了一种大规模生产重组DDAH的方法和一种进行HTS的测定方法。正如我们最近在《生物分子筛选》杂志上发表的文章中所描述的，我们的策略通过发现几种调节DDAH酶活性的新型小分子而结出了果实。这对我来说特别令人兴奋，因为DDAH已被证明主要参与肺损伤小鼠模型中肺纤维化的进展，并且发现在特发性肺纤维化（IPF）患者的肺组织中上调。这两个重要环节：DDAH及其在IPF中的作用，以及调节DDAH活性的小分子的发现，激发了我对开发一种恢复肺功能的新疗法的兴趣。工作环境：正如我的建议中所描述的，我的研究由于在斯坦福大学进行而大大加速;这是一个拥有多个药理学，分子和细胞研究核心设施的一流研究环境。此外，斯坦福大学培养多学科合作，并高度致力于将基础研究转化为临床有用的治疗。斯坦福大学的两个例子是SPARK和Bio-X研究项目。可能从这种转化研究工作中受益的领域之一是IPF。在斯坦福大学，有一些小组正在积极努力了解IPF的病理生物学和潜在治疗方法的开发。其中一个小组是我的共同导师罗森博士的实验室，该实验室正在研究治疗IPF的不同靶点。他们在这方面的专门知识对我的项目很有价值。此外，斯坦福大学提供了几个相关的课程和研讨会，包括心脏病研究进展;药物开发和未来的教师，这对我的职业发展非常感兴趣。研究：IPF是一种侵袭性和不可治愈的疾病，会逐渐破坏肺的正常结构。尽管IPF发生和进展的确切病因和事件顺序仍不完全，但新出现的数据表明DDAH活性失调可能在该疾病的发病机制中起关键作用。最近在博来霉素诱导的IPF样肺损伤的动物模型中进行的机制研究（通过IPF患者的肺组织验证）表明DDAH主要参与疾病过程。值得注意的是，用DDAH抑制剂（L- 291）治疗博来霉素攻击的小鼠可改善纤维化并恢复肺功能。此外，对人肺组织的分析显示，IPF患者的DDAH显著升高。因此，如我的研究提案中所述，靶向这一途径可能具有一定的治疗潜力。调节DDAH过度活化的一种方式是通过使用直接抑制其酶活性的小分子拮抗剂。因此，我们对DDAH的几种小分子拮抗剂（包括FDA批准的（用于其他适应症））的发现和验证值得进一步研究用于治疗开发。职业目标：实际上，药物开发是一个漫长的过程（平均12年），需要对疾病机制的基本理解和药物的优化，以选择性和有效地靶向感兴趣的疾病。因此，我的近期目标是使用基于小分子的方法研究DDAH作为IPF药物靶点的可行性。如果这项研究的结果是令人鼓舞的，那么我将瞄准我的长期职业目标，通过形成一个合作网络来合成和测试最有前途的化合物的几种类似物，并破译这种药物调节DDAH活性的机制，来逐步优化药物先导物。我计划继续药物发现和开发道路，最终目标是进行临床试验，并开发一般慢性肺部疾病（特别是IPF）的治疗方法。因此，NHLBI的研究科学家发展奖将为我提供一个无与伦比的机会，发展我在生物医学研究领域的职业生涯，并为科学界带来创新。拟议中的研究是在一个领域的主要利益NHLBI和可行的斯坦福大学的研究环境和奉献精神和专业知识的所有人员在这个项目中挖掘。 (End摘要）